T1141 Preventive Effect of Lansoprazole and Famotidine on Gastric Mucosal Injury Induced by Low-Dose Aspirin in H. pylori-Negative Healthy Volunteers

Abstract

Background/Aims: Recent studies have revealed that interindividual differences in metabolic disposition of non-steroidal anti-inflammatory drugs (NSAIDs) are associated with risk of NSAID-induced gastrointestinal mucosal injury. Individuals with poor metabolizer alleles of either or both CYP2C8 (such as CYP2C8*3) or CYP2C9 (such as CYP2C9*2 or CYP2C9*3), whichmetabolize NSAIDs, show increased risk of developing acute or chronic gastrointestinal injury on using NSAIDs. However, precise estimation of the metabolic profile of NSAIDs in an individual by combination of single nucleotide polymorphisms is difficult due to the variety of enzymes involved in NSAID metabolism. Given that 13CO2 is known to be produced on the metabolization of 13C-labeled naproxen ([13C]-naproxen), we examined whether or not the [13C]-naproxen breath test can be used to predict naproxen-induced gastric mucosal injury. Methods: Fifteen H. pylori-negative healthy volunteers (CYP2C9*1/ *1, n=13; CYP2C9*1/*3, n=2) ingested 300 mg of [13C]-naproxen, after which breath samples were collected over a period of 48 hours. Changes from baseline in carbon isotope ratios (13CO2/12CO2) in carbon dioxide were measured and expressed as a delta-overbaseline (DOB) ratio (‰), and plasma PGE2 and TXB2 were also measured at the same time. Gastric mucosal injury based on the modified Lanza score (MLS) was evaluated before and after twice daily dosing of naproxen 300 mg for 2 days. Results: At baseline, the median MLS was 0 (range: 0-1). After twice daily dosing with naproxen 300 mg for 2 days, however, MLS ranged from 1 to 5. Subjects were classified into one of three groups based on MLS level: patients with MLS of 1 or 2 were designated as mild (n = 5), MLS 3 as moderate (n = 7), and MLS 4 or 5 as severe (n =3). The AUC0-120min of DOB was 6.55 ± 0.31 h*‰ for the mild group, 5.45 ± 0.45) h*‰ for the moderate group, and 4.04 ± 0.97) h*‰ for the severe group; the AUC0-120min of DOB in the mild group was significantly higher than that in the severe group (P < 0.05). Overall, CYP2C9*1/*3 participants showed MLSs which fell in the severe group and had lower AUC0-120min of DOB values and lower rates of PGE2 and TXB2 than CYP2C9*1/*1 participants. Conclusion: [13C]-naproxen breath test results were significantly correlated with naproxen-induced mucosal injury, suggesting the usefulness of this test as a predictive determinant of naproxen-induced gastric mucosal injury.